The present invention relates to novel N-[substituted aryl]-N'-(substituted alkoxy)-urea and thiourea derivatives useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds, and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention prevent the intestinal absorption of cholesterol in mammals by inhibiting the enzyme acyl-coenzyme A (Acyl-CoA):cholesterol acyltransferase (ACAT).
The atheromatous plaque, which is the characteristic lesion of atherosclerosis, results from deposition of plasma lipids, mainly cholesteryl esters, in the intima of the arterial wall. Progressive enlargement of the plaque leads to arterial constriction and ultimately coronary heart disease. A number of clinical trials have shown a causal relationship between hypercholesterolemia and coronary heart disease.
Agents that control dietary cholesterol absorption moderate serum cholesterol levels. Dietary cholesterol is absorbed from the intestinal lumen as free cholesterol which must be esterified with fatty acids. This reaction is catalyzed by the enzyme acyl-CoA: cholesterol acyltransferase (ACAT). The resulting cholesteryl esters are packaged into the chylomicrons which are secreted into the lymph. Inhibitors of ACAT not only prevent absorption of dietary cholesterol but also prevent the reabsorption of cholesterol which has been released into the intestine through endogenous regulatory mechanisms, thus lowering serum cholesterol levels and ultimately counteracting the formation or development of atherosclerosis.
Copending U.S. Ser. No. 147037, filed Feb. 5, 1988, now abandoned describes certain substituted urea, thiourea, carbamate, and thiocarbamate compounds as potent ACAT inhibitors.
Copending U.S. Ser. No. 176079, filed Mar. 30, 1988, pending, describes certain N-[(2,6-disubstituted)phenyl]-N'-diarylalkyl]ureas as potent ACAT inhibitors.
Copending U.S. Ser. No. 175089, filed Mar. 30, 1988, pending describes certain N-[[2,6-disubstituted)phenyl]-N'-arylalkyl]ureas as potent ACAT inhibitors.
Copending U.S. Ser. No. 176080, filed Mar. 30, 1988, now U.S. Pat. No. 4,868,210 describes certain N-2,6-dialkyl or N-2,6-dialkoxyphenyl-N'-arylalkylurea compounds as potent ACAT inhibitors.
However, the compounds disclosed in the aforementioned copending United States applications do not suggest or disclose the combination of structural variations of the compounds of the present invention described hereinafter.